A retrospective survey was conducted in hematologic centres of the Rete Ematologica Lombarda (REL) on 529 older AML patients seen between 2020-2022. Compared to 2008-2016, the use of intensive ...chemotherapy (ICT) decreased from 40% to 18.1% and of hypomethylating agents (HMAs) from 19.5% to 13%, whereas the combination of Venetoclax/HMA, initially not available, increased from 0% to 36.7%. Objective treatment-specific fitness criteria proposed by SIE/SIES/GITMO in 2013 allow an appropriate choice between ICT and HMAs by balancing their efficacy and toxicity. Venetoclax/HMA, registered for patients unfit to ICT, has a unique toxicity profile because of prolonged granulocytopenia and increased infectious risk. Aiming at defining specific fitness criteria for the safe use of Venetoclax/HMA, a preliminary investigation was conducted among expert REL hematologists, asking for modifications of SIE/SIES/GITMO criteria they used to select candidates for Venetoclax/HMA. While opinions among experts varied, a general consensus emerged on restricting SIE/SIES/GITMO criteria for ICT-unfit patients to an age limit of 80-85, cardiac function > 40%, and absence of recurrent lung infections, bronchiectasis, or exacerbating COPD. Also, the presence of an adequate caregiver was considered mandatory. Such expert opinions may be clinically useful and may be considered when treatment-specific fitness criteria are updated to include Venetoclax/HMA.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
Peripheral blood (PB) hematopoietic progenitor cells (HPC) collected by apheresis are the first‐choice source for allogeneic stem cell transplantation. The target HPC dose is usually ...considered to be 4 × 106 CD34+ cells/kg of the recipient, but higher doses are required in reduced‐intensity conditioning and haploidentical transplants. Thus, prolonged stimulation and repeated collections or failure to reach HPC target may occur, increasing risks for donors and recipients. We carried out a retrospective multicenter study on healthy donors, to identify donor variables which may correlate with HPC mobilization.
Study Design and Methods
HPC allogeneic donations from sibling and unrelated donors performed in two centers from 1995 to 2012 were analyzed. We defined a mobilization cutoff of 50 × 106 CD34+ cells/L and tested somatic variables, blood counts, and granulocyte–colony‐stimulating factor (G‐CSF) dose and molecular form.
Results
A total of 360 donors were analyzed (male, 201; female, 159; sibling, 348; unrelated, 12; median range age, 44.8 13‐80 years). Median peak CD34+ in PB was 54.4 × 106/L (range, 5 × 106‐299 × 106). By multivariate analysis, we identified the following variables to correlate with good mobilization: 1) male sex (p < 0.0005); 2) younger age (p = 0.007); 3) higher baseline (premobilization) white blood cell (WBC) count (p < 0.0005); 4) higher G‐CSF dosage (p < 0.0005); and 5) use of lenograstim rather than filgrastim (p < 0.002).
Conclusion
In healthy donors it is possible to predict successful HPC mobilization by donor sex, age, WBC count, and G‐CSF form and dose. Furthermore, based on these data, it may be possible, at least in parental setting, to modulate G‐CSF dosage on the basis of donor characteristics.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Introduction: In elderly acute myeloid leukemia (AML) patients (pts) the debate about the use of intensive chemotherapy (iC) as opposed to non-intensive therapy (niT) or best supportive care (BSC) is ...a hot topic, particularly after the introduction of venetoclax (VEN) use. Age, comorbidities, functional impairment, therapy benefits and risks, pts preferences, and AML features influence this choice. The SIE/SIES/GITMO (“fitness”) criteria (Ferrara, 2013) are a valuable and comprehensive tool, but a revalidation is needed in the light of the new treatment options. Methods: Within the Rete Ematologica Lombarda (REL), we evaluated 1) the concordance between “fitness” of pts, and the type of treatment they actually received, 2) the overall survival (OS) according to the “fitness”, to the prognostic European Leukemianet (ELN17) stratification and to the treatment received, and 3) the presence of other parameters, as Charlsons Comorbidity Index (CCI), potentially useful in therapy decision. Pts were classified as fit to iC (FIT), unfit to iC (UNFIT), or unfit even to niT (FRAIL), as defined by the SIE/SIES/GITMO criteria. Results: From Jan 20 to Dec 22, 503 AML pts (53% de-novo), with a median age of 76 years (y) (range, 65-93) were diagnosed consecutively at 11 Hematology Units. According to “fitness” criteria, 25% of pts were FIT, 61% UNFIT, and 14% FRAIL (Table1). Median age was significantly lower in FIT pts (70 y), as compared to UNFIT (78 y) and FRAIL (79 y) (p <0.0001). Overall, the concordance between “fitness criteria” and the treatment actually received by pts was 75.9% (71% in FIT, 76% in UNFIT and 84% in FRAIL). After a median follow-up of 12 months (m), median OS of the whole population was 7.4 m. Median OS of FIT, UNFIT and FRAIL pts was 13.7, 7.2 and 1.4m, respectively (p <0.0001, Fig 1a). According to physicians' decision, 18% of pts received iC, 55% niT, mainly hypomethylating agents (HMA: azacytidine or decitabine) + VEN, and 27% BSC. Median OS was 17m, 10.2m, 1.4m in iC, niT and BSC pts, respectively (p<0.0001, Fig 1b). According to ELN17, evaluable in 73% of pts, 19% were favorable (fav), 20% intermediate (int) and 61% adverse (adv), without differences into “fitness” groups. Median OS was significantly worse in ELN adv than in ELN fav and int (p: 0.001 and p: 0.002, respectively, Fig 1c). In FIT pts, median OS was 17m with iC and 11.4m with niT (VEN-HMA) (p: 0.3). The use of iC was associated with younger age (median age: 69 in iC vs 73 y in niT, p<0.0001), lower CCI (CCI< 2: 88.5% in iC vs 64% in niT, p: 0.0032) and not significantly with better ELN risk (ELN adv 49% in iC pts vs 70% in niT, p: 0.07). The use of iC or niT did not affect remission rate (64% vs 71%) nor OS in different ELN risk groups. In UNFIT pts, median OS was 14m with niT and 3.8m with BSC pts (p<0.0001). The use of niT compared to BSC was associated with younger age (median 77 vs 81 y; p<0.0001), not adv ELN risk (41% vs 7%, p: 0.0001), lower ECOG performance status (PS) and CCI (PS<2: 81% vs 65%, p: 0.0001; CCI<2: 66% vs 50%, p: 0.038). In UNFIT pts treated with VEN-HMA median OS was 11m vs 7.3m with HMA only (p: 0.019). The use of VEN-HMA rather than HMA only was associated with younger age (median: 76 vs 80 y; p: 0.0045), better PS and CCI (PS<2: 94% vs 84%, p: 0.026; CCI<2: 68% vs 50%, p: 0.008). ELN risk distribution was similar. In non-adv risk pts, OS was 17m with VEN-HMA, significantly better compared to HMA only (7m) (p: 0.03) as well as to adv risk pts treated with VEN-HMA (p: 0.0017). Age >82y, number of comorbidities, lack of caregiver were the most frequent reasons for the physician's preference for HMA therapy over VEN-HMA. InFRAIL pts, median OS was 2.9 m with niT and 1.1m with BSC pts (p: 0.04). The use of niT was associated with a relatively better PS and younger age (<73 y). At multivariable analysis, ELN fav and iC favorably affected survival, whereas a FRAIL fitness status, PS>2, and CCI>2 proved to be independent adverse prognostic factors. Conclusion: Fitness stratification of SIE/SIES/GITMO correlated to pts's survival and were useful in the decision-making approach of treatment also in the new drugs era. Within the “fitness” categories, age, CCI and particularly ELN risk, had an impact on the choice of the type of induction therapy, in FIT pts (iC vs niT) without changing the outcome, while in UNFIT pts an under-treatment worsened OS. These preliminary data should be implemented with a longer follow-up and a larger sample size.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
INTRODUCTION
Acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutation is a poor prognosis disease, with a high rate of relapse and poor OS, even after allogeneic hematopoietic ...cell transplantation (alloHCT).
In recent years FLT3 inhibitors have emerged in the treatment of FLT3-ITD AML both as monotherapy and in combination with standard chemotherapy; they were used both during induction therapy and in relapsed or refractory disease. They have also been used as maintenance therapy after transplantation.
FLT3 inhibitors act by blocking the proliferative boost due to FLT3-ITD.
Some of these drugs are approved for the treatment of solid cancers such as hepatocellular carcinoma, renal cell carcinoma and differentiated thyroid carcinoma.
We report the case of a patient with FLT3-ITD-positive AML whose disease relapsed after alloHCT as a myeloid sarcoma and who was successfully treated with Sorafenib.
CASE REPORT
A 54-year old male was diagnosed with AML with a normal karyotype and FLT3-ITD and NPM1 mutations. A molecular complete response (CR) was observed after “3+7” induction therapy. A consolidation therapy with Citarabine was administered and then alloHCT was performed. Conditioning was tBu-Flu and donor was an HLA-identical sibling. Cyclosporine and short term Methotrexate were used as Graft Versus Host Disease (GVHD) prophylaxis.
No sign of acute GVHD occurred, molecular CR was confirmed at bone marrow evaluation at day +100, thereafter CSPA was tapered.
Nine months after alloHCT a left pectoral subcutaneous nodule appeared. The biopsy consisted with myeloid sarcoma; molecular analysis revealed that sarcoma was FLT3-ITD positive. Meanwhile many sarcomas quickly appeared in different areas of the body and patient referred tingle in his right leg. A CT-PET scan showed pathological uptake in cervical lymph nodes, in subcutaneous and muscular lesions at left upper limb, right hip, thighs, and at right tibia bone. At the same time bone marrow exam confirmed molecular CR and full donor chimerism.
Immunosuppression was stopped and he was admistered Sorafenib 200 mg twice for day in off-label use 11 months after alloHCT. Superficial lesions and right leg tingle decreased within 7 days and no lesion was detected by physical examination after 10 weeks of therapy; CT-PET scan after 8 weeks showed partial remission.
Sorafenib was increased to 400 mg twice for day and the expected side effects occurred, namely diarrhoea and palmar-plantar erythrodysesthesia.
After four months of therapy with Sorafenib, he was treated with donor lymphocyte infusion (DLI), the drug was continued and no clinical manifestation of GVHD appeared. He received a second dose of DLI after seven weeks from the first dose.
After 23 weeks of Sorafenib treatment and two dose of DLI, sarcomas localization continued to slowly decrease, bone marrow exam confirmed molecular CR and full donor chimerism, and patient was in good physical condition, with limited oral chronic GVHD.
CONCLUSION
Our observation is the proof of Sorafenib activity even in FLT3-ITD myeloid sarcoma, and of his ability to reach extramedullary tissue and to be effective against sarcoma myeloblasts. This experience suggest to look for FLT3 mutation in myeloid sarcoma tissue and to consider therapy with FLT3-inhibitors, alone or in association with chemotherapy.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction : For patients affected by acute myelogenous leukemia (AML) with normal karyotype, the presence of a mutation in FLT3-ITD identifies a subgroup of individuals with poor prognosis for ...whom allogenic transplantation in first complete remission is indicated; such therapy is not required in patients with mutations in NPM1 or CEPBA. The present study evaluated the impact of mutations in FLT3 on post-allogenic transplantation outcomes in patients with cytogenetically normal AML.
Methods : A total of 68 patients with normal karyotype AML underwent to allogenic stem cell transplantation at our Department from March 2006 to March 2017. Median age was 51 years (range 15-70); there were 45 males and 23 females. The conditioning regimen was TBI or BU based regimen for full-dose transplantations, while TT-FLU-MEL was used in patients undergoing reduced intensity conditioning. Cyclosporine and short-term methotrexate was used as prophylaxis for graft versus host disease (GVHD) for transplantation with an HLA identical family member or unrelated donors. For haploidentical transplants, a post-transplantation infusion of cyclophosphamide (50 mg/kg) was administered at days +3 and +4 followed by mycophenolate mofetil and cyclosporine. All patients were investigated for mutations in the FLT3, NPM1, and CBPA genes.
Results : Conditioning was full-dose in 46 patients, and reduced intensity 17 cases. In 5 patients, a haploidentical transplant was used. 38 patients were transplanted in first complete remission and 20 in second complete remission, while 10 were transplanted with active disease. Overall survival (OS) of the entire cohort was 57% with an event-free survival (EFS) of 54%. The main cause of death was recurrence of disease (n=19); 10 patients died of non-relapse mortality. All patients who were transplanted with active disease died.
Considering the results of molecular characterization, 20 patients had a mutation in FLT3-ITD (FLT3+), while 48 did not (FLT3-). The presence of a mutation in FLT3-ITD was not associated with age, conditioning regimen, or donor type; 80% of FLT3+ patients were in first complete remission compared to 45% of FLT3- patients. OS in the FLT3+ subgroup was 35%, with a relapse rate of 45% (9/20); OS in the FLT3- subgroup was 66%, with a relapse rate of 25% (12/48). There were no differences in OS or EFS in the FLT3- subgroup among those undergoing transplantation during first or second complete remission.
Signs and symptoms of chronic GVDH (cGVHD) were observed in 25 of 55 evaluable patients (37%); of these, 20 patients were FLT3- and 5 were FLT3+. The presence of cGVHD was associated with better survival in FLT3- patients; in fact, 8/21 (38%) patients without signs of cGVHD had relapse compared to 4/20 (20%) with cGVHD (p=0.02). In FLT3+ patients, 4/9 (44%) without cGVHD had relapse vs. 3/5 (60%) of those with cGVHD (p=0.78).
Conclusions : The present data suggest that patients with mutations in FLT3 have a greater risk of relapse than FLT3- patients, although additional studies in larger patient groups are needed. The different impact of cGVDH in OS in the two groups appears to suggest different post-transplant strategies, reserving the use of donor leukocyte infusion for FLT3- patients with relapse or at high risk of relapse, and using FLT3 inhibitors in the subset of FLT3+ patients as they are at high risk.
No relevant conflicts of interest to declare.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
Treatment outcome of patients with acute myeloid leukemias (AML) with complex karyotype (CK), defined as the presence of 3 or more cytogenetic abnormalities, is very poor because of high relapse ...rate. Prognosis can be improved to some extent by allogeneic stem cell transplantation in eligible patients, whose feasibility in advanced age patients is now expanding thanks to the improvement of transplantation techniques.
We analyzed cytogenetic features and clinical outcomes of 65 newly diagnosed AML patients with CK according to 2017 European Leukemia Net recommendations who presented to our center between August 1995 and June 2016.
The median age was 61 years (range 31-80); the median number of cytogenetic aberrations was 7 (range 3-94). The most frequent cytogenetic abnormalities are summarized in Table 1.
Fifty-nine patients out of 65 (91%) received standard chemotherapy (mainly based on cytarabine and anthracycline), 6 (9%) other non intensive therapeutic regimens (hypomethylating agents in 5 patients). Twenty-seven patients (42%) achieved complete haematologic remission (CR) after 1 (23%), 2 (16%) or 3 (3%) induction cycles. Among these, 13 (48%) relapsed in a median time of 5 months (range 1-20).
Among the 42 patients considered eligible, allogeneic stem cell transplantation (allo-HCT) was performed in 16 patients (38%), 8 of these (50%) relapsed in a median time of 6 months (range 2-107). Patients who developed chronic graft-versus-host disease (n = 6) showed a trend towards a longer median overall survival (128 months) when compared to patients who did not experienced it (13 months) (p. 055). There were no differences in survival for patients who underwent transplantation after 1 or 2 induction chemotherapy cycles or in first or second CR.
Patients who were not eligible for allogeneic transplantation because of age or comorbidities had a median overall survival of 5 months (range 1-16) if treated with standard chemotherapy and 10 months (range 2-14) if treated with non intensive chemotherapy regimens.
Overall, with a median follow-up of 93 months (range 18-182), 6 patients out of 65 (9%) were alive at the time of analysis, all after allogeneic stem cell transplantation. Forty-four patients (68%) died due to disease, 12 (18%) for early toxicity during chemotherapy, 3 (19%) because of non relapse mortality after transplantation.
Allogeneic stem cell transplantation performed in CR represents the only possibility of cure for patients affected by AML with CK. Because of the positive effect of chronic graft-versus-host disease on survival, it seems appropriate to evaluate strategies as donor lymphocyte infusion (DLI) to prevent relapse in these high-risk AML patients. Considering the best overall survival observed with hypomethylating agents compared to intensive chemotherapy, we suggest identifying allo-HCT eligibile patients as soon as possible, so to adress them to intensive chemotherapy and to use hypomethylating therapy in those who are not candidate for allo-HCT.
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No relevant conflicts of interest to declare.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Peripheral blood (
PB
) hematopoietic progenitor cells (
HPC
) collected by apheresis are the first‐choice source for allogeneic stem cell transplantation. The target
HPC
dose is usually ...considered to be 4 × 10
6
CD
34+ cells/kg of the recipient, but higher doses are required in reduced‐intensity conditioning and haploidentical transplants. Thus, prolonged stimulation and repeated collections or failure to reach
HPC
target may occur, increasing risks for donors and recipients. We carried out a retrospective multicenter study on healthy donors, to identify donor variables which may correlate with
HPC
mobilization.
Study Design and Methods
HPC
allogeneic donations from sibling and unrelated donors performed in two centers from 1995 to 2012 were analyzed. We defined a mobilization cutoff of 50 × 10
6
CD
34+ cells/
L
and tested somatic variables, blood counts, and granulocyte–colony‐stimulating factor (
G
‐
CSF
) dose and molecular form.
Results
A total of 360 donors were analyzed (male, 201; female, 159; sibling, 348; unrelated, 12; median range age, 44.8 13‐80 years). Median peak
CD
34+ in
PB
was 54.4 × 10
6
/
L
(range, 5 × 10
6
‐299 × 10
6
). By multivariate analysis, we identified the following variables to correlate with good mobilization: 1) male sex (p < 0.0005); 2) younger age (p = 0.007); 3) higher baseline (premobilization) white blood cell (
WBC
) count (p < 0.0005); 4) higher
G
‐
CSF
dosage (p < 0.0005); and 5) use of lenograstim rather than filgrastim (p < 0.002).
Conclusion
In healthy donors it is possible to predict successful
HPC
mobilization by donor sex, age,
WBC
count, and
G
‐
CSF
form and dose. Furthermore, based on these data, it may be possible, at least in parental setting, to modulate
G
‐
CSF
dosage on the basis of donor characteristics.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
