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SummaryThe management of acute myeloid leukaemia (AML) in India remains a challenge. In a two‐year prospective study at our centre there were 380 newly diagnosed AML (excluding acute promyelocytic leukaemia, AML‐M3) patients. The median age of newly diagnosed patients was 40 years (range: 1–79; 12·3% were ≤ 15 years, 16·3% were ≥ 60 years old) and there were 244 (64·2%) males. The median duration of symptoms prior to first presentation at our hospital was 4 weeks (range: 1–52). The median distance from home to hospital was 580 km (range: 6–3200 km). 109 (29%) opted for standard of care and were admitted for induction chemotherapy. Of the 271 that did not take treatment the major reason was lack of financial resources in 219 (81%). There were 27 (24·7%) inductions deaths and of these, 12 (44·5%) were due to multidrug‐resistant gram‐negative bacilli and 12 (44·5%) showed evidence of a fungal infection. The overall survival at 1 year was 70·4% ± 10·7%, 55·6% ± 6·8% and 42·4% ± 15·6% in patients aged ≤15 years, 15 ‐ 60 years and ≥60 years, respectively. In conclusion, the biggest constraint is the cost of treatment and the absence of a health security net to treat all patients with this diagnosis.

There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens.

Impact of FLT3 mutations and secondary cytogenetic changes on the outcome of patients with newly diagnosed acute promyelocytic leukemia treated with a single agent arsenic trioxide regimen Ninety-eight newly diagnosed cases of PML-RARα α positive APL were treated with a regimen of single agent ATO. FLT3 activating mutations were seen in 33% and an additional cytogenetic finding was noted in 23.2%. FLT3 activating mutations were significantly associated with a bcr3 PML-RARα α isoform (p=0.012) and a delay in achieving a molecular remission (p=0.022). Neither FLT3 activating mutations nor secondary cytogenetic changes had an impact on clinical outcome. Haematologica 2007; 92:994-995 The efficacy of arsenic trioxide (ATO) in the management of relapsed and newly diagnosed cases of acute promyelocytic leukemia (APL) has been established.

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Summary:Allogeneic bone marrow transplant recipients have severe impairment of cell-mediated immunity and hence a higher incidence of mycobacterial infections might be expected in regions where tuberculosis is common. We reviewed the case records of 217 patients who underwent allogeneic bone marrow transplantation during the period 1986-1999 at our center in India. Mycobacterial infections were diagnosed in three patients (1.38%). All patients presented with extrapulmonary disease. Two patients had disseminated tuberculosis with one of these being diagnosed on autopsy studies. The third patient had tuberculosis involving the cervical lymph node and dorsal spine. Two patients treated with antituberculous therapy are well. Infection with Mycobacterium tuberculosis is not a common problem in allogeneic bone marrow recipients even in an endemic area, but when it occurs, it is usually disseminated with predominantly extrapulmonary involvement. Bone Marrow Transplantation (2001) 27, 973-975.

Mesenchymal stem cells (MSCs) are an alluring therapeutic resource because of their plasticity, immunoregulatory capacity and ease of availability. Human BM-derived MSCs have limited proliferative capability, consequently, it is challenging to use in tissue engineering and regenerative medicine applications. Hence, placental MSCs of maternal origin, which is one of richest sources of MSCs were chosen to establish long-term culture from the cotyledons of full-term human placenta. Flow analysis established bonafied MSCs phenotypic characteristics, staining positively for CD29, CD73, CD90, CD105 and negatively for CD14, CD34, CD45 markers. Pluripotency of the cultured MSCs was assessed by in vitro differentiation towards not only intralineage cells like adipocytes, osteocytes, chondrocytes, and myotubules cells but also translineage differentiated towards pancreatic progenitor cells, neural cells, and retinal cells displaying plasticity. These cells did not significantly alter cell cycle or apoptosis pattern while maintaining the normal karyotype; they also have limited expression of MHC-II antigens and are Naive for stimulatory factors CD80 and CD 86. Further soft agar assays revealed that placental MSCs do not have the ability to form invasive colonies. Taking together all these characteristics into consideration, it indicates that placental MSCs could serve as good candidates for development and progress of stem-cell based therapeutics.

Summary:A fludarabine-based protocol (fludarabine (25 mg/m 2 / day  6 days), cyclophosphamide (10 mg/kg/day  2 days) and ATG (ATGAM 10 mg/kg/day  4 days)) was used in four multiply transfused Fanconi's anemia (FA) patients aged 5-15 years to reduce rejection during allogeneic bone marrow transplantation (BMT). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mini methotrexate. The graft source was G-CSF-stimulated bone marrow or peripheral blood stem cells (PBSC) in two patients each. All patients engrafted with median time to ANC4500/mm 3 being 14 days (range: 12-17) and unsupported platelet count 420 ,000/mm 3 being 13 days (range: 11-18). One patient had secondary graft rejection on day 56 and expired on day 69 due to fungal pneumonia. One patient who developed acute myeloid leukemia on day 56 underwent successful induction with cytosine and daunorubicin followed by peripheral blood stem cell (PBSC) rescue on day 70 and is presently in remission with complete donor chimerism and grade I GVHD. At a median follow-up of 13 months (range: 4-21), three patients (75%) are well with complete donor chimerism. Addition of fludarabine to the conditioning regimen for BMT in FA can provide additional immunosuppression for engraftment without increasing toxicity. Allogeneic bone marrow transplantation (BMT) has produced excellent survival rates in patients with Fanconi's anemia (FA) using low-dose cyclophosphamide with or without radiation therapy. 1 Graft rejection rates of 30-60% occur in multiply transfused patients with aplastic anemia requiring intensification of immunosuppression. 2 Few case reports exist on the use of fludarabine-based protocols as conditioning regimens for patients with FA with encouraging results 3-8 and we describe our experience in multiply transfused FA patients. Patients and methodsBetween 1999 and 2003, four male patients with FA underwent six antigen-matched sibling or family donor BMT at our center. The diagnosis of FA was confirmed by stress cytogenetics using mitomycin C and all had a bone marrow aspirate suggestive of aplastic anemia done 3-6 months prior to BMT. Standard karyotyping was not performed. Conditioning regimen consisted of fludarabine 25 mg/m 2 /day (day À11 to À6); cyclophosphamide 10 mg/ kg/day for 2 days (days À7 and À6), antithymocyte globulin (ATGAM, Pharmacia Upjohn, USA) 10 mg/kg/ day for 4 days (days À5 to À2). Graft source was either G-CSF-stimulated bone marrow or G-CSF-stimulated peripheral blood stem cells (PBSC) in two patients each. Supportive carePatients were nursed in HEPA-filtered rooms with adequate sterile precautions and barrier nursing. G-CSF (5 mg/ kg/day) was started on day þ 7 following the infusion of bone marrow or PBSC. Broad-spectrum antibiotics and antifungals were administered as per existing protocols for febrile neutropenia. Acyclovir and Septran were administered as CMV and Pneumocystis carinii prophylaxis, respectively. Ganciclovir was administered started as preemptive prophylaxis if the CMV polymerase chain r...