INTRODUCTION About 50% of HCL patients (pts) relapse after chemotherapy with purine analogs (PA). After identifying the BRAF-V600E mutation as the genetic cause of HCL (Tiacci et al. NEJM 2011), we ...documented a high efficacy of the BRAF inhibitor vemurafenib in R/R pts (Tiacci, Park et al. NEJM 2015), especially when added to rituximab (Tiacci et al. NEJM 2021). HCL expresses bright CD20 and obinutuzumab (OBI) is a more effective anti-CD20 agent than rituximab (RTX) in other indolent B-cell neoplasms such as chronic lymphocytic leukemia and follicular lymphoma. RTX produces ~20% complete remissions (CR) in R/R HCL (Kreitman, ASH Educ Program 2012), while OBI activity in this setting is unknown. METHODS In the ongoing academic, phase-2, multi-center trial HCL-PG04, R/R HCL pts needing treatment due to cytopenia(s) received OBI 1000 mg intravenously on days 1-8-15 of cycle 1 and on day 1 of cycles 2-6 (1 cycle = 28 days). CR required resolution of cytopenias (platelets ≥ 100,000/mmc; neutrophils ≥ 1500/mmc; hemoglobin ≥ 11 g/dl), no palpable splenomegaly and no leukemic cells on morphologic analysis of the bone marrow biopsy, as assessed one month after the last OBI dose. Minimal residual disease (MRD) was analyzed by BRAF-V600E specific PCR in the bone marrow aspirate (sensitivity: 0.05% mutant alleles). RESULTS We enrolled 26 pts (M/F 24/2; median age 62 years, range 39-80) with a median of 2 prior therapies (range 1-7), including 7 refractory to PA (26%) and 2 to RTX (8%). Median values of disease burden parameters at baseline were: 70% BM HCL infiltration, 830 neutrophils/mmc, 62000 platelets/mmc, 14 g/dl hemoglobin, and 16 cm of longest spleen diameter (in 16/26 splenomegalic patients; 1 pts. had been splenectomized and 9 were not splenomegalic at baseline). Toxicity was as expected, largely of grade (G) 1-2, always reversible and mainly consisting in: infusion reactions (G1-2 92%; G3 4%, in a single pt allergic to previous RTX who discontinued OBI); asymptomatic increase of liver enzymes (G1-2 19%; G3 GGT 15%; G3 ALT 4%); transient worsening of baseline G1-G3 thrombocytopenia to G3 (23%) or G4 (35%), with only 1 minor bleeding (4%, G1 epistaxis); transient neutropenia (G2 4%; G3 15%; G4 15%); and rare infections (G1-2 herpes labialis 8%; G3 pneumonia 4%). CR was reached in 12/25 evaluable pts (48%), including 2 pts with incomplete platelet recovery (~70000-90000/mmc) and 2 pts with delayed resolution of palpable splenomegaly. Notably, CR was achieved in 5/7 pts refractory to PA and 1/2 pts refractory to RTX. Furthermore, CR was negative for MRD in 9/12 pts (75%, including 3 pts with delayed MRD clearance), something never observed with vemurafenib. However, the kinetics of cytopenia resolution was slower compared to our previous vemurafenib trial, in that in pts obtaining CR with OBI neutrophil recovered to ≥1500/mmc after a median of 7 weeks (vs 4 weeks with vemurafenib) and platelets recovered to ≥100000/mmc after a median of 8 weeks (vs 2 weeks with vemurafenib). Prior exposure to RTX (n=12 pts) did not compromise OBI efficacy (5 CR, all MRD-negative, in 11 evaluable pts). In pts achieving CR with OBI, progression-free and MRD-free survival were both 100% at 56 months (range 20-66) and 48 months (range 6.5-60) of median follow-up, respectively (Fig.1). The 13 non-CR pts (minor response 7; no response 3; progression 3) were effectively salvaged with another course of OBI combined with vemurafenib, which will be presented at the meeting. CONCLUSIONS OBI frequently produced deep and durable responses in R/R HCL, to an extent apparently greater than RTX, thus qualifying as an active and safe chemotherapy-free strategy in this setting.
Highlights ► We report the role of azacitidine in t-MDS after NHL. ► Four patients were treated with aza: 3/4 obtained a response. ► Azacitidine is a possible strategy for t-MDS.
From the Division of Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto I, University "La Sapienza" of Rome, Italy (CC, GAB, GMDE, MB, GA, RF); Hematology, ...Azienda Ospedaliera S. Eugenio, Rome, Italy (PN); Italian Association against Leukemia, Lymphoma and Myeloma (AIL) (FM); Istituto Studi Direzionali (ISTUD), Milan, Italy (MGM, AN)
Correspondence: Claudio Cartoni, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto I, via Benevento 6, 00161 Rome, Italy. E-mail: cartoni{at}bce.uniroma1.it
The costs of home care (HC) programs may be tailored to the specific needs of patients with hematological malignancies. The aim of this study was to analyze the use of resources and the costs of a program of HC for four different prognostic groups of patients subdivided according to disease status. Over 2 years, 144 patients with hematological malignancies were assisted at home. Patients were subdivided according to disease status and life expectancy in the following groups: (i) terminal phase, with a life expectancy of 3 months or less; (ii) advanced phase, with a life expectancy of 6 months or less; (iii) chronic phase, with a life expectancy of more than 6 months; (iv) discharged early from the hospital with curable disease, following anticancer chemotherapy. Median mean monthly costs (MMC) in Euro ( ) have been compared with the costs of hospitalization (DRG). Among the 4 groups of patients, those discharged early and in terminal phase required the highest mean monthly number of home visits (27.2 and 24.1), transfusions (6.1 and 6.8) and days of care (22.8 and 19.7) respectively. MMC were affected by the following variables: disease status and transfusion requirements. MMC for terminal patients (4,232.50 ) and those discharged early (3,986.40 ) were higher than those for advanced (2,303.80 ) and chronic patients (1,488,30 ). The cost of HC was lower than the corresponding DRG charges, but exceeded the district fares for HC of cancer patients. In hematological patients, the costs of HC differ according to disease status and transfusion requirements. For some categories of patients, costs of HC are lower than those of hospitalization, although higher than the current national fares for HC programs.
Key words: home care, supportive care, palliative care, hematological malignancies.
Introduction. Hairy cell leukemia (HCL) is a rare clonal B-cell chronic lymphoproliferative disorder. Current treatments for HCL include purine analogs (PA), which are used successfully as front-line ...therapy in young and fit patients. The therapeutic armamentarium has been recently extended by the introduction of rituximab, BRAF oral inhibitors and other novel agents. Interferon alpha (IFNα) has been the first agent capable of inducing a response in HCL patients and of changing the natural course of the disease. It has been extensively used up to the introduction of PA. Nowadays, IFNα front-line is limited to pregnant women (or desiring a pregnancy), to patients with severe neutropenia or frail, or to relapsed/refractory patients. We hereby report the experience of 74 patients treated continuously with IFNα at our Center in Rome.
Methods. A retrospective analysis was performed on patients with HCL or with variant HCL treated between 1990 and 2020 with IFNα until progression or toxicity. The initial dosage was 3 MUI subcutaneously three times weekly (3d/week). In responding patients, after 12 months the dose was progressively tapered to reach a very low maintenance dose, ranging from 0.1 MUI 3d/week to 0.9 3d/week. After 12 months of treatment, the degree of response was based on peripheral blood count evaluation, bone marrow biopsy and IFNα front-line; C) patients resistant to PAs who received IFNα as second or further line of treatment.
Results. After 12 months of treatment, 70 patients (95%) achieved either a PR or a CR in 52 (70%) and 18 (24%) cases, respectively. Four (5.4%) patients were considered as non-responders. After a median follow-up of 92 months (range 7-236), 55 patients (75%) still maintained their response while receiving maintenance IFNα. The estimated 5-year and 10-year PFS were 89% and 77%, respectively (Fig. 1). The median PFS for these patients has not been reached at 10 years. Patients in CR at 12 months of treatment showed a significantly superior PFS rate (p 0.001). The 10-year PFS was 94% for patients in CR compared to 73% for patients who obtained a PR during abdominal ultrasound. The mutational status of BRAF V600E by PCR analysis was assessed in a subset of patients during treatment. Three groups of patients were identified: A) patients >65 years who received IFNα front-line; B) patients <65 years with comorbidities or women desiring a pregnancy who received IFNα therapy. Univariate analysis showed a different PFS for groups A, B and C, the 5-year PFS being 95%, 68% and 96%, respectively (p 0.005) (Fig. 1). In group A, a CR was achieved by 28% of cases and a PR by 62%, in group B the rates were 16% and 80%, and in group C 28% and 68%, respectively. Group C received a median number of 2 prior lines of treatment; 89% received PAs. Patients with previous PA-based treatment obtained a PR in 55% of cases and a CR in 32%. No significant differences were observed in terms of PFS in the 10 patients with a variant HCL (p 0.5); 1/10 achieved a CR. The impact of Hb, WBC count, spleen size and platelet count were assessed in univariate analysis. A significant difference in the entire case series was observed in patients with a WBC >3500/mmc at the start of treatment: the estimated median PFS was 236 vs 108 months (p 0.004). Twenty-two patients in response during IFNα maintenance were tested for MRD basing on BRAF status: 32% were negative during treatment (7 out of 22). All patients with negative MRD were in CR. G1-2 extra-hematologic toxicity, occurred as flu-like syndrome and fatigue, was observed in 25 patients (76% in group A), 13/25 patients discontinued IFNα for toxicity; 1 case of alopecia was reported. No patient required discontinuation due to G3-4 hematologic toxicity. Four deaths occurred, 2 due to secondary neoplasms and 2 in very elderly patients.
Conclusions. IFNα still retains a role in selected HCL patients. In young patients with comorbidities front-line IFNα remains a possible option, although not as effective as PAs. In elderly patients, the continuous administration allows remarkable results with acceptable toxicity. Also in patients resistant to PAs, INFα is capable of inducing durable responses in a considerable part of patients. The data on MRD demonstrate the possibility of achieving a molecular response. Although the role of IFNα is further limited by the advent of new agents, when administered in a continuous schedule it still represents a valid therapeutic option in specific subsets of HCL patients.
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Martelli:sandoz: Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; celgene: Membership on an entity’s Board of Directors or advisory committees; roche: Consultancy, Membership on an entity’s Board of Directors or advisory committees; gilead: Consultancy, Membership on an entity’s Board of Directors or advisory committees; janssen: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Foà:Abbvie: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Roche: Membership on an entity’s Board of Directors or advisory committees; Roche: Membership on an entity’s Board of Directors or advisory committees. Tiacci:Roche: Research Funding; Abbvie: Other: Travel and meeting expenses. Pulsoni:Pfizer: Consultancy; Merk: Consultancy; Takeda: Consultancy; Gilead: Speakers Bureau; Sandoz: Consultancy; roche: Consultancy, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.
Summary
Little is known of the course of COVID‐19 and the antibody response to infection or vaccination in patients with hairy‐cell leukaemia (HCL). Among a total of 58 HCL cases we studied in these ...regards, 37 unvaccinated patients, mostly enjoying a relatively long period free from anti‐leukaemic treatment, developed COVID‐19 between March 2020 and December 2021 with a usually favourable outcome (fatality rate: 5/37, 14%); however, active leukaemia, older age and more comorbidities were associated with a worse course. Postinfection (n = 11 cases) and postvaccination (n = 28) seroconversion consistently developed, except after recent anti‐CD20 or venetoclax therapy, correlating with perivaccine B‐cell count. Vaccination appeared to protect from severe COVID‐19 in 11 patients with breakthrough infection.
We report on epidemiology, features, outcome, and domiciliary management of pain in patients with advanced hematological malignancies followed by an experienced hospital-based home care (HC) team. ...Out of 469 patients, 244 (52%) experienced a total of 284 pain syndromes. Pain intensity was rated from mild to moderate in 31% and from moderate to severe in 69% of them. The diagnosed pain mechanisms were deep somatic in 56%, superficial somatic in 15%, visceral 14%, mixed 8%, and neuropathic in 7% of pain syndromes, respectively. Incident pain was observed in 38% of all pain syndromes. In every diagnostic group, deep somatic pain was prevalent. Moreover, 85% of visceral pain syndromes were observed in patients affected by non-Hodgkin's lymphoma (NHL). In addition, out of 284 pain syndromes, 150 (51%) were caused by bone involvement. The most frequent recognized pain provocative mechanisms were bone marrow expansions, osteolysis, lymph node enlargement, and mucositis. In our experience, an approach based on the association of causal therapies and analgesics allows optimal control of most pain syndromes. Therefore, pain is a major problem in patients affected by advanced hematological malignancies, and its management can be effective and feasible when carried out by a skilled HC team.
BACKGROUND Hairy cell leukemia (HCL) is a BRAFV600E-mutated indolent B-cell neoplasm (Tiacci et al., NEJM 2011) often relapsing after chemotherapy with purine analogs. BRAF inhibition is very active ...in relapsed/refractory (R/R) HCL, but produces mostly partial remissions (PR) and never clears minimal residual disease (MRD) (Tiacci, Park, et al., NEJM 2015). In a recent phase-2 single-center study on 30 R/R patients (pts) with a median of 3 prior therapies, a short chemotherapy-free regimen of the BRAF inhibitor vemurafenib (V) + rituximab (R; Mabthera) led to 87% complete remissions (CR), 60% MRD-negativity and 85% relapse-free survival (RFS) at a median follow-up of 34 months, with a favorable toxicity profile (Tiacci et al., NEJM 2021). METHODS A multi-center retrospective study was conducted to validate in a real-world setting the off-label use of V+R in R/R HCL needing therapy due to cytopenia(s). RESULTS From 6/2019 to 12/2021, 35 pts (median age 56 years, range 42-80) were treated at 14 Italian centers with VR (V: 960 mg bid for 8 weeks; R: 375 mg/m2 every 2 weeks for 8 doses); biosimilar R was used in 89% of pts. Prior therapies (median 2; range 0-11) included chemotherapy with cladribine or pentostatin (94% of pts), interferon-alpha (29%), rituximab (31%), splenectomy (6%), BRAF inhibitor monotherapy (6%) and zanubrutinib (3%). Median blood counts across the 35 pts were: platelets 69000/mmc, neutrophils 860/mmc and hemoglobin 11.6 g/dl (with 20% of pts, i.e. 7/35, requiring transfusions). Eleven pts (31%) had active (n=3) or latent (n=8) infections, including: ongoing systemic atypical mycobacteriosis (n=1); ongoing miliary tuberculosis (n=1; a 80-year old pt who was the only one receiving V+R as first-line therapy); ongoing large cerebral abscess (n=1); HIV infection controlled by anti-viral therapy (n=1); and latent tuberculosis (n=1) or HBV (n=6) infections requiring anti-microbial prophylaxis. Toxicity was as expected, mostly of grade 1-2 and always reversible (Table), allowing high relative dose intensities (RDI) for both drugs (V, median 97%; interquartile range/IQR 73-100%; R, 100% in 85% of pts). Similarly, among the 33/35 (94%) pts who received V for a substantial duration (≥35 days), and were thus evaluable for dose density, 20 pts (61%) completed V without ever suspending the drug, including 14/33 pts (42%) without any dose reduction. Vemurafenib toxicities were mainly represented by cutaneous rash, asymptomatic liver and pancreatic laboratory abnormalities, arthralgia, warts and photosensitivity. Three pts (9%) were not evaluable for response as they died prematurely due to atypical mycobacteriosis, complications of neurosurgery for cerebral abscess and sudden death unrelated to study drugs. Recovery of platelets (≥100000/mmc), neutrophils (≥1500/mmc) and hemoglobin (≥ 11 g/dl) occurred quickly, after a median of 2, 4 and 7 weeks after starting treatment, respectively. A CR was observed in 30/32 evaluable cases (94%; or 86%, 30/35 pts, by intention to treat/ITT). CR was obtained in all evaluable cases refractory to chemotherapy (n=8) or rituximab (n=3), or previously splenectomized (n=2) or unable to reach CR with a prior BRAF inhibitor (n=2). The only 2 evaluable pts not achieving a CR (1 PR; 1 short-lived resolution of cytopenias) received V at only 16%/50% RDI and R at only 13%/34% RDI due to drug toxicities. Analysis of MRD by allele-specific PCR for BRAF-V600E in the bone marrow aspirate was performed in 30 pts and showed MRD clearance (<0.05% mutant alleles) at a high rate: 79% (22/28 CR pts; or 65%, 22/35 pts, by ITT), which raised to 82% (66% by ITT) when including 1 additional CR case untested by PCR which had negative bone marrow flow cytometry. At a median follow-up of 21 months after the end of treatment, RFS was high among the 31 responding pts, with just 1 relapse (3%) in the only case obtaining a PR post-therapy (Figure). CONCLUSIONS This study validates in a real-life context the high efficacy and tolerability of the V+R chemo-free regimen delivered to R/R HCL pts, including the cost-saving use of biosimilar rituximab.
Background. The epidemiology of pain in patients with advanced haematological malignancies followed at home, 469 consecutive patients has been followed over a six years.
Methods. Each pain syndrome ...(PS) was properly assessed and treated according to the WHO ladder. The pain intensity was reported by a Numerical Analogue Scale, which rated score ranging from 0 (no pain) to 10 (the most severe), or, in less complaint patients, by a verbal description. Each PS was classified as deep somatic, superficial somatic, neuropathic and mixed or unknown.
Results. Of 469 patients, 258 (55%) were males; the median age was 67 (4–95) years. Out of 469 patients, 244 (52%) experienced almost one PS, for a total of 284, which intensity was rated from mild to moderate in 92 (31%) and from moderate to severe in 192 (69%) of them respectively. The 244 patients who experienced pain were significantly younger than those without pain (57 ± 21 versus 69±16, P< 0.0005). Moreover, the group of less than 20 old years patients presented a higher incidence of pain compared to others (85% versus 49%, P=0.0007). The patients affected by Multiple Myeloma (MM), Acute Lymphoblastic Leukaemia (ALL), non Hodgkin's Lymphomas (NHL) and Blastic Crisis showed a higher incidence of pain compared to other disease groups (P=0.0011). Among acute leukemias, ALL patients presented a higher incidence of pain compared to those affected by myeloblastic forms (79% versus 41%, P= 0.0002). An effective pain control was achieved within 24 hours in 259/284 (92%) without any admission. PS was diagnosed as deep somatic, superficial somatic, visceral, neuropathic and mixed (somatic + neuropathic) in the 56 %, 15 %, 14 %, 7 % and 8 % of the PS respectively. A higher incidence of deep somatic pain was recorded in all diagnosis groups. Moreover, out of the 39 visceral PS, 33 (85%) have been recorded among patients with NHL and 6 (15%) in the others (P=0.0001). MM patients presented a higher rate of the incident pain (P<0.001). The causative mechanisms of PS were directly referable to underlying diseases, to their clinical complications and to concomitant and unrelated conditions in the 69%, 22% and 9% of cases respectively. The most involved sites were: the spine (27%), the abdomen (20%), the legs (15%), the thorax (11%) and orofaringeal tract (10%).
Conclusion. our data show that pain is a relevant problem in advanced onco-haematological patients, which mostly present disease-related PS, reflecting specific pathological activity of the underlying malignancy.
Table 1Incidence of pain and distribution of pain syndromes among the haematological malignanciesMalignancyPP/TP (No)Incidence of pain (%)Pain Syndromes (No)MM35/399038ALL31/397940NHL77/1286089BC29/565234HD5/11455CLL10/244211AML28/694134MDS20/633222CMPD5/33188Others3/7433Total243/46952284PP: Pain Patients; TP: Total Patients, No: number, MM: Multiple Myeloma, ALL: Acute Lymphoblastyc Leukemia, NHL; Non Hodgkin's Lymphomas; BC: Blastic Crisis, HD: Hodgkin's Disease, CLL: Chronic Lymphocytic Leukemia, Acute Myeloblastyc Leukemia, MDS: Myelodysplastyc Syndromes, CMPD: Chronic Myeloproliferative Disorders.
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