The cost of multiple myeloma and its complications: A single-center study from Oran, Algeria.

BACKGROUND: The expenses of multiple myeloma (MM) represent a real economic and societal burden for patients and health authorities. However, very little is known about the situation in Algeria. Therefore, the aim of this study is to evaluate the costs generated by the management of MM and its complications in Algerian patients. MATERIALS AND METHODS: An observational retrospective study conducted on patients diagnosed with MM, from January 1st, 2019 to April 31st, 2023, at the Establishment Hospitalier Universitaire November 1st, Oran. A bottom-up costing methodology was used to assess the phase-specific cost and the complication burden. RESULTS: In total, 249 qualified for the study. For autologous stem cell transplantation (ASCT) eligible patients, the mean per patient cost of treating myeloma was estimated at: induction regimen ($4072); ASCT ($2899); consolidation ($1538); and maintenance ($355.76). The mean drug cost for ASCT-ineligible patients was $1421. The use of generic bortezomib and generic melphalan has led to a reduction in expenses of $1,075,181 ($5,024 per patient; 55.35%) and $10,864 ($487 per patient; 15.07%), respectively. Another cost-saving adaptation was ASCT using non-cryopreserved (NC) stem cells. The cost of managing MM complications was $177,782 per year. CONCLUSION: A number of adjustments have been implemented to the management of MM over time to improve clinical efficacy and reduce costs in Algeria. However, this may have come with a startlingly high cost of complications.

HLA-B*58 and HLA-B*27 Play a Role in the Development of Acute Leukemia: A Case Control Study.

BACKGROUND: Acute leukemia (AL) constitutes a group of malignant hematological diseases with multifactor origins. Some human leukocyte alleles (HLA) may be important genetic risk factors for development of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). It is still unknown whether there is a relationship between ALL and AML with some alleles of the major histocompatibility complex. Our study looks specifically at western and southwest Algerian populations. METHOD: Using the polymerase chain reaction with the sequence specific probe (PCR- SSP) method, we investigated the relationship of HLA-B alleles in 163 Algerian AL patients and 293 controls from the same ethnic origin. The study ran from 2013 - 2020. RESULTS: Allele frequencies of HLA-B*27 and HLA-B*58 was higher in AL patients compared with control individuals; p=0.05 and p=0.03 respectively. Interestingly, all patients carrying HLA-B*27 allele and 88% of patients carrying HLA-B*58 allele had AML. However, there were no significant differences when we compared these results with the rest of AL group (HLA-B*X allele) (p=0.387). Response to induction chemotherapy treatment were comparable between the two patient groups 67% and 65% (p=0.978) respectively. CONCLUSION: These results suggest that the HLA-B*27 and HLA-B*58, may be factors predisposing individuals to acute leukemia, in west and southwest Algerian patients. A large-scale study is still needed to confirm these findings.

[Second allogeneic (update). Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Deuxième allogreffe (mise à jour). Recommandations de la Société francophone de greffe de moelle osseuse et de thérapie cellulaire (SFGM-TC).

Relapse after allogeneic hematopoietic cell transplantation (allo-HCT) remains a major concern because it is associated with poor survival. A second allo-HCT is a valid option in this situation. During the 13th annual harmonization workshops of the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to update the second allo-HCT recommendations elaborated during the previous workshop (2016). The main indication for a second allo-HCT remains relapse of initial hematologic malignancy. Disease status; complete remission (CR), and relapse time after the first allo-HCT>6 months impact positively the overall survival of patients after the second allo-HCT. Donor change is a valid option, particularly if there is HLA loss on leukemic cells after a first haploidentical or following a mismatched allo-HCT is documented. Reduced intensity conditioning is recommended, while a sequential protocol is a reasonable option in patients with proliferative disease. A post-transplant maintenance strategy after hematological recovery is recommended as soon as day 60, even if the immunosuppressive treatment has not yet been stopped. Hypomethylating agents, and targeted therapies such as anti FLT3, anti BCL2, anti-IDH1/2, TKI, anti-TP53, anti-CD33, anti-CD19, anti-CD22, anti-CD30, check point inhibitors, and CAR-T cells can be used as a bridge to transplant or as an alternative treatment to the second allo-HCT.

[Acute lymphoblastic leukemia in developing countries: Management from the transplant indication (allo/auto) until post-transplant follow-up. Guidelines from the SFGM-TC]. / Leucémie aiguë lymphoblastique dans les pays en voie de développement : prise en charge dès l'indication de greffe jusqu'au suivi post-greffe. Recommandations de la SFGM-TC.

Management of acute lymphoblastic leukemia (ALL) patients in countries with limited resources depends on the means of prognostic stratification, available treatment and logistics. During the 12th annual harmonization workshops of the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to elaborate unified guidelines for allogeneic hematopoietic cell transplantation (Allo-HCT) in this disease. Conventional poor prognostic factors can be used to determine the indication of allo-HCT in first remission. Patients lacking a HLA-matched related donor can be allografted with a haploidentical donor allo-HCT if available. Chemotherapy based conditioning regimen can be used if TBI is not available, because the probability to find a radiotherapy department with the capacity for total body irradiation is low. For patients with Philadelphia chromosome positive (Phi+) ALL, post-transplantation tyrosine kinase inhibitors as a systematic maintenance strategy is recommended. Autologous HCT is optional for Phi+ ALL patients with negative minimal residual disease, who not eligible for allo-HCT. Patients with refractory/relapsed disease have a poor prognosis which highlights the importance of acquiring in the future new therapies such as: blinatumumab, inotuzumab, and CAR-T cells.

Efficacy and safety of autologous transplant with non-cryopreserved peripheral blood stem cells in myeloma and lymphoma in Algeria. 10 years' experience.

INTRODUCTION: The storage of harvested stem cells, in standard refrigerators at +4°C, is a simple and inexpensive alternative to cryopreservation for most patients living in countries with limited resources. We present the 10 years' experience of our single center from Oran in Algeria using non-cryopreserved stem cells after conditioning with high dose chemotherapy, in a large group of myeloma and lymphoma patients. METHODS: From May 2009 to December 2019, autologous stem cell transplantation (ASCT) was carried out in our center, of which 420 with multiple myeloma (MM) and 154 patients with lymphoma. The source of stem cells in all patients consisted of mobilized autologous peripheral blood stem cells (PBSCs). A median of one cytapherisis was performed (range, 1-3) and the products of the aphaeresis were stored in a conventional blood bank refrigerator at +4°C, in 300-mL transfer packs (Baxter Healthcare) composed of impermeable gas, polyvinyl chloride plastic film. The viability of the harvested cells is assessed by flow cytometry using 7'AAD (7 Amino-Actinomycine D) and was determined by a trypan blue dye exclusion test. The chemotherapy conditioning regimen (Mel200, BEAM, CBV, EAM, BeEAM) started once a minimum of 2×106 CD34+cell/kg in MM or 3x106 CD34+cell/kg in lymphoma was obtained. RESULTS: In MM patients, the median age at ASCT was 54 years (range; 27-73). The median harvested CD34+ cell count was 3,2x106/kg (range; 1, 22 to 13, 22) and the viability in all cases being >90%. All patients had engraftment on the median of day 9 (range; 7 to 24) and platelet transfusion independence on the median of day 13 (range; 9 to 39). There was no graft failure. Transplant related mortality (TRM) at 100 days was 3,5%. The overall response to transplant was 99% (complete remission (CR) =64,5%; very good partial remission (VGPR) =34%, partial remission (PR) =1,5%). The estimated overall survival (OS) at 5 years was 68% and the median post-transplant progression-free survival (PFS) was 47 months. On December 31th 2021, 41% patient relapsed and 28% died after disease progression. 305 (75%) patients are alive and 237 (59%) without disease activity after a median follow-up of 52 months (range; 13 to 149). In lymphoma patients, 98 Hodgkin`s lymphoma (HL) and 56 non-Hodgkin´s lymphoma (NHL), were auto grafted. The median age at ASCT was 28 years (range; 16-55) and 33 years (17-61) respectively. After mobilization a median of 4,25x106/kg (NHL) and 4,14x106/kg (HL) of CD34+ was infused and the median viability of the cells after 7 days of refrigeration (trypan blue exclusion) was 82%. The median time to achieve 0,5 G/L neutrophil or more was 14 days (9-44) and 15 days (11-27) in HL and NHL, median time to achieve 20 G/L platelets or more at a median of 16 days (10-37) and 17 days (15-28) in HL and NHL. The OS at 5 years was 76% and 67% for patients with HL and NHL respectively. Transplant related mortality at 100 days was 5% in HL and 12,5% in NHL. CONCLUSION: This study demonstrates the feasibility of intensified therapy followed by autologous non-cryopreserved PBSCs infusion in MM and lymphoma patients. This method of ASCT is cheaper, and may potentially enable the widespread use of ASCT activities in other hematology centers in Algeria and in developing countries.

Impact of the Major BCR-ABL1 Transcript Type on Clinical and Biological Parameters and Molecular Response in Patients With Chronic Myeloid Leukemia.

AIM: In chronic myeloid leukemia (CML), the impact of MBCR-ABL1 major transcript type on disease phenotype and response to treatment still controversial to date. This work aims to study the influence of Mb3a2 and Mb2a2 transcripts on clinico-biological parameters and the molecular response in patients with chronic phase chronic myeloid leukemia (CP-CML) treated with Imatinib as frontline therapy. METHODS: This is six years prospective study started in March 1 st, 2013. 67 patients with newly CP-CML were treated by Imatinib as frontline therapy. Clinical and biological characteristics disease were collected for all patients. Molecular typing was performed by multiplex RT-PCR and quantification of transcripts by real-time quantitative PCR (qRT-PCR). The cumulative incidence of deep molecular response (DMR) was estimated by the Kaplan-Meier method. The comparison was made using the parametric Log-Rank test. A value of P ≤ 0.05 is considered significant. RESULTS: 61% of patients expressed b3a2, 35.82% b2a2 and 2.98% expressed a rare transcript of type e19a2. At diagnosis, the b2a2 type had a higher level of expression than that of b3a2 (67.92 vs 53.79%; P = 0.03). This insignificant difference between the two transcript subgroups was also observed for rates below 1% at 6 months (54 vs 39; P = 0.26) and below 0.1% (54 vs 44 %; P = 0.50), (77 vs 50%; P = 0.09) and (81 vs 78 %; P = 0.52) at 12, 18 and 24 months respectively. The two types of transcript had almost the same kinetics. Nevertheless, the absolute value of the BCR-ABL1/ABL ratio decrease was faster in the group of patients expressing b3a2, than in those expressing b2a2. At 18 months post IM therapy, patients with a b3a2 transcript have a trend of better MMR that those with b2a2 (77 vs 50%; P = 0.09). The DMR was not significantly different between two groups at 24 months (50 vs 32%; P = 0.20) and 36 months (75 vs 70%; P = 0.54) respectively. The cumulative probability of achieving MRD at 5 years was higher in patients with b3a2 type but not statistically significant; (85 vs. 68%; P = 0.17). CONCLUSION: Patients with b3a2 transcript may be associated with a better response to Imatinib therapy.

[Establishment of Hematopoietic cell transplantation program in developing countries : Guidelines from the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC)]. / Mise en place d'un programme de greffe de cellules souches hématopoïétiques dans les pays en voie de développement. Recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Hematopoietic cell transplantation (HCT) is the curative treatment for many malignant and non-malignant blood disorders and some solid cancers. However, transplant procedures are considered tertiary level care requiring a high degree of technicality and expertise and generating very high costs for hospital structures in developing countries as well as for patients without health insurance. During the 11th annual harmonization workshops of the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to elaborate unified guidelines, for developing the transplant activity in emerging countries. Access to infrastructure must comply with international standards and therefore requires a hospital system already in place, capable of accommodating and supporting the HCT activity. In addition, the commitment of the state and the establishment for the financing of the project seems essential.

[Management of patients developing acute gastro-intestinal graft-versus-host-disease: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Prise en charge de la GVH digestive aiguë : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Graft-versus-host disease (GVHD) is the most common complication after allogeneic hematopoietic cell transplantation (allo-HCT) with a frequency range of 30% to 50%. GVH is the leading cause of non-relapse-related deaths and a cause early mortality. Gastro-intestinal (GI) GVH results in digestive manifestations that involve the small intestine and the colon. The patient may then have diarrhea, intestinal bleeding, abdominal pain but also clinical signs such as nausea and vomiting may lead to anorexia. GI-GVHD promotes undernutrition as well as significant losses of vitamins and trace elements. In the case of post-transplant diarrhea, differential diagnosis can include GI-GVHD, infection and drug toxicity. Although, corticosteroids w/wo calcineurin inhibitors represent the standard of care in first line treatment, there is no consensus regarding salvage therapy in case of corticoresistant GI-GVH. In addition, assessment of early nutritional status would help combating undernutrition, which is an independent risk factor for mortality in patients with GI-GVHD. In this workshop of the Fancophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) we focused on the management of patients developing GI-GVHD following allo-HCT.

[Second allogeneic hematopoietic stem cell transplant: Guidelines from the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC)]. / Seconde allogreffe : recommandations de la Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Disease recurrence and graft dysfunction after allogeneic hematopoietic stem cell transplantation (allo-HSCT) currently remain among the major causes of treatment failure in malignant and non-malignant hematological diseases. A second allo-HSCT is a valuable therapeutic option to salvage those situations. During the 8th annual harmonization workshops of the french Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to elaborate unified guidelines on feasibility, indications, donor choice and conditioning in the case of a second allo-HSCT. In case of relapse, a second allo-HSCT with reduced intensity or non-myeloablative conditioning is a reasonable option, particularly in patients with a good performance status (Karnofsky/Lansky>80%), low co-morbidity score (EBMT score≤3), a longer remission duration after the first allo-HSCT (>6 months), and who present low disease burden at the time of second allo-HSCT. Matched related donors tend to be associated with better outcomes. In the presence of graft dysfunction (primary and secondary graft rejection), an immunoablative conditioning regimen is recommended. A donor change remains a valid option, especially in the absence of graft-versus-host disease after the first allo-HSCT.

[Stem cell transplantation unit: Guidelines from the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC)]. / Unité de greffe : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Allogeneic hematopoietic cell transplantation (HCT) is part of the standard of care for many hematological diseases. Over the last decades, significant advances in patient and donor selection, conditioning regimens as well as supportive care of patients undergoing allogeneic HCT leading to improved overall survival have been made. In view of many new treatment options in cellular and molecular targeted therapies, the place of allogeneic transplantation in therapy concepts must be reviewed. Most aspects of HCT are well standardized by national guidelines or laws as well as by certification labels such as FACT-JACIE. However, the requirements for human resources, construction and layout of a unit treating patients during the transplantation procedure and for different complications are not well defined. Here, we describe the process of planning a transplant unit in order to open a discussion that could lead to more precise guidelines in the field of personnel and infrastructural requirements for hospitals caring for people with severe immunosuppression.

[Preventative and therapeutic relapse strategies after allogeneic hematopoietic stem cell transplantation: Guidelines from the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC)]. / Stratégies préventives et thérapeutiques de la rechute après allogreffe de cellules souches hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Disease relapse remains the first cause of mortality of hematological malignancies after allogeneic hematopoietic stem cell transplantation (allo-HCT). The risk of recurrence is elevated in patients with high-risk cytogenetic or molecular abnormalities, as well as when allo-HCT is performed in patients with refractory disease or with persistent molecular or radiological (PET-CT scan) residual disease. Within the frame of the 7th annual workshops of the francophone society for bone marrow transplantation and cellular therapy, the working group reviewed the literature in order to elaborate unified guidelines for the prevention and treatment of relapse after allo-HCT. For high risk AML and MDS, a post transplant maintenance strategy is possible, using hypomethylating agents or TKI anti-FLT3 when the target is present. For Philadelphia positive ALL, there was a consensus for the use of post-transplant TKI maintenance. For lymphomas, there are no strong data on the use of post-transplant maintenance, and hence a preemptive strategy is recommended based on modulation of immunosuppression, close follow-up of donor chimerism, and donor lymphocytes infusion. For multiple myeloma, even though the indication of allo-HCT is controversial, our recommendation is post transplant maintenance using bortezomib, due to its a good toxicity profile without increasing the risk of GVHD.

Hematopoietic stem cell transplantation in Algeria.

INTRODUCTION: Algeria is a country of 40.4 million inhabitants and half of which is under 30years. In Algeria, Health-care insurance covered, 90% of the population. Health care is free and it is supported by the Ministry of Health. 16 university hospitals exist in Algeria and only two (Algiers and Oran) practicing bone marrow transplant. Adult hematologic malignancies account for 10% (about 4000 new cases/year) of the malignancy affecting in most cases young patients under 65years of age. In 2016, 270 transplants were performed in total (Algiers+Oran), including 149 allografts (related donor transplants: 99%) and 121 autografts. 98% of transplants are done in adults and only 2% in children with cord blood transplants. In summary for the two transplant centers, the predominant types of transplantation performed are allogeneic transplant in 55% and autologous transplant in 45%. The particularity of EHU1st November in Oran, is the use of non-cryopreserved stem cells. Stem cell was mobilized using G-CSF alone and the grafts were kept in a conventional blood bank refrigerator at +4°C until reinfusion on day 0. The outcome with non-cryopreserved stem cells are the same as those with cryopreserved stem cells and we conclude that autologous transplant with non cryopreserved hematopoietic stem cells (HSC) is a simple, effective and safe method and the cryopreservation is not necessary in our work conditions in developing countries. The projects are achieving the autograft in all University Hospitals with non cryopreserved HSC, achieving a center allograft in the east of the country and the development of bone marrow transplantation in children. CONCLUSION: Currently in Algeria, the number of transplantation is insufficient and the development of new transplant centers is essential. In the future, we hope to implement the National Society of Bone Marrow transplant and also the National recipient registry and Donor registry in Algeria.

[Haploidentical hematopoietic stem cell transplantation: Guidelines from the Francophone society of marrow transplantation and cellular therapy (SFGM-TC)]. / Greffe de cellules-souches hématopoïétiques haplo-identiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Haploidentical hematopoietic stem cell transplantation (HSCT) is being increasingly used due to improvement of the transplantation procedures allowing a reduction of graft-versus-host-disease (GVHD) and of transplant-related mortality (TRM). Such improvements have been particularly observed after administration of T-replete HSCT graft associated to an in vivo T cell depletion by the administration of high-doses of cyclophosphamide (HD-Cy) after transplantation. Here, we have analyzed the results of haplo-identical T replete HSC transplants, in particular, when performed with post-transplant HD-Cy in order to provide recommendations for the clinical practice. Criteria of choice for a haploidentical donor by priority order are absence of donor-specific antibodies (DSA) and to prioritize: CMV seronegative recipient/donor couples, ABO matching in case of deserythrocytation, male donor for a male recipient, the youngest donor. There is no clear argument in favor of the use of bone marrow versus peripheral blood stem cells (PBSC) after non myeloablative conditioning regimen, while after ablative conditioning PBSC seem to be associated with higher risks of GVHD without obvious impact on survival. Results of haploidentical HSCT, confirmed by several groups, are interesting in lymphomas (in particular Hodgkin disease) and for acute leukemia. Outcomes of patients rely on age, disease status at transplant and conditioning intensity. At equivalent disease risk, results of haploidentical HSCT seem comparable to those of HLA matched HSCT, raising the question of the classification of such transplants as alternatives. In all cases, we recommend to include patients in prospective clinical trials.